Resistance to chemotherapeutic drugs is a significant problem in the treatment of
colorectal cancer, resulting in low response rates and decreased survival. Recent studies have shown that
shikonin, a
naphthoquinone derivative, promotes apoptosis in
colon cancer cells and
cisplatin-resistant ovarian cells, raising the possibility that this compound may be effective in
drug-resistant
colorectal cancer. The aim of this study was to characterize the molecular mechanisms underpinning
shikonin-induced apoptosis, with a focus on endoplasmic reticulum (ER) stress, in a 5-fluorouracil-resistant
colorectal cancer cell line, SNU-C5/5-FUR. Our results showed that
shikonin significantly increased the proportion of sub-G1 cells and DNA fragmentation and that
shikonin-induced apoptosis is mediated by mitochondrial Ca2+ accumulation.
Shikonin treatment also increased the expression of ER-related
proteins, such as
glucose regulatory
protein 78 (
GRP78), phospho-
protein kinase RNA-like ER
kinase (PERK), phospho-
eukaryotic initiation factor 2 (eIF2α), phospho-phosphoinositol-requiring protein-1 (IRE1), spliced X-box-binding protein-1 (XBP-1), cleaved
caspase-12, and
C/EBP-homologous protein (CHOP). In addition,
siRNA-mediated knockdown of CHOP attenuated shikonininduced apoptosis, as did the ER stress inhibitor
TUDCA. These data suggest that ER stress is a key factor mediating the cytotoxic effect of
shikonin in SNU-C5/5-FUR cells. Our findings provide an evidence for a mechanism in which ER stress leads to apoptosis in
shikonin-treated SNU-C5/5-FUR cells. Our study provides evidence to support further investigations on
shikonin as a therapeutic option for 5-fluorouracil-resistant
colorectal cancer.